OVERALL DESCRIPTION (Abstract of the application) This program project combines the efforts of four investigators to utilize murine models to study hematopoiesis. The investigators are drawn from several disciplines but they share the common goals of defining the role of the systems they are studying on hematopoiesis. Dr. Shaun Coughlin whose primary interest is in cardiovascular disease and has previously cloned the thrombin receptor gene will study the effect of mutation of this gene on megakaryocytic and platelet biology. Dr. Y. W. Kan whose interest is in erythropoiesis has isolated two NFE-2 related genes which are expressed in diverse tissues including the hematopoietic tissues. He will now study the function of this gene and the effects of their deletions on hematopoiesis. Dr. Clifford Lowell who has been studying a group of tyrosine kinase genes will utilize the homologous recombination technology to study the effects of knockout of these genes and to determine the relative important roles of these tyrosine kinases in hematopoietic cells of various lineages. Dr. Maria Pallavicini whose longstanding interest is in murine hematopoiesis will utilize a novel receptor-mediated retrovirus vector strategy to study the receptors present in hematopoietic cells of various lineages and the specific transduction expression of genes in these lineages with a view to rescue mice defective in hematopoiesis. These projects are highly interactive, as they all share the murine model and common techniques such as hematopoietic stem cell isolation and culture, bone marrow trans- plantation, transgenic mice, and homologous recombination. The program is directed by Y. W. Kan who has longstanding interests in hematology research and co-directed by Marc Shuman who, in addition to his research work on platelet glycoproteins and urokinase, has been responsible for the hematology fellowship program at UCSF. The environment for research at UCSF is excellent, as there is a wide basic science and clinical base to complement research in this area. The techniques for studying stem cells and transgenic animals have been established in the two cores which will further facilitate exchanges between the investigators. Therefore, it is expected that the interactions of these investigators in the environment provided will be mutually beneficial and will result in greater contributions to the study of hematopoiesis than would occur if these projects were pursued individually.